There are many diseases or disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is inadequate efficacy and/or the prevalence of side effects. Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation is also a common cause of pain.
The enzyme cyclooxygenase (COX) converts arachidonic acid to an unstable intermediate, prostaglandin H2 (PGH2), which is further converted to other prostaglandins, including PGE2, PGF2α, PGD2, prostacyclin and thromboxane A2. These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity, including pro-inflammatory effects. The COX enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and another that in mast cells and tissues is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).
Among all prostaglandin metabolites, PGE2 is particularly known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE2, including “NSAIDs” (non-steroidal anti-inflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE2. However, the inhibition of COXs has the disadvantage of reducing the formation of all metabolites of PGH2, thereby decreasing the beneficial properties of some of the metabolites. In view of this, drugs which act by inhibition of COXs are suspected to cause adverse biological effects. For example, the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function. Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE2 in inflammation. The conversion of PGH2 to PGE2 by prostaglandin E synthases (PGES) may, therefore, represent a pivotal step in the propagation of inflammatory stimuli. There are two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES). mPGES-1 is an inducible PGES after exposure to pro-inflammatory stimuli. mPGES-1 is induced in the periphery and CNS by inflammation, and represents therefore a target for acute and chronic inflammatory disorders. PGE2 is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes. Arachidonic acid is transformed by the action of prostaglandin H synthase (PGH synthase, cycloxygenase) into PGH2 which is a substrate for mPGES-1, the terminal enzyme transforming PGH2 to the pro-inflammatory PGE2.
Agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE2, are beneficial in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also beneficial in the treatment of asthma and COPD.
Blocking the formation of PGE2 in animal models of inflammatory pain results in reduced inflammation, pain and fever response (Kojima et. al, The Journal of Immunology 2008, 180, 8361-6; Xu et. al., The Journal of Pharmacology and Experimental Therapeutics 2008, 326, 754-63). In abdominal aortic aneurism, inflammation leads to connective tissue degradation and smooth muscle apoptosis ultimately leading to arotic dilation and rupture. In animals lacking mPGES-1 a slower disease progression and disease severity has been demonstrated (Wang et. al., Circulation, 2008, 117, 1302-1309).
Several lines of evidence indicate that PGE2 is involved in malignant growth. PGE2 facilitates tumor progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression. In support of a role for PGE2 in cancers, genetic deletion of mPGES-1 in mice suppresses intestinal tumourogenesis (Nakanishi et. al., Cancer Research 2008, 68(9), 3251-9). In human beings, mPGES-1 is also upregulated in cancers such as colorectal cancer (Schroder, Journal of Lipid Research 2006, 47, 1071-80).
International Publication Number WO 2013/186692 discloses triazolone compounds of formula (I) (disclosed as formula (III) in the specification of WO 2013/186692)

wherein,
X1, X2 and X3 are each independently selected from CH and N;
P is selected from —CH2NHC(O)— and —CH2NHS(O)2—;
Q is selected from C1-8alkyl, haloC1-8alkyl, C1-8alkoxyC1-8alkyl, hydroxyC1-8alkyl, carboxylC1-8alkyl, C3-12cycloalkyl, C6-14aryl, 3-15 membered heterocyclyl, and 5-14 membered heteroaryl;
each occurrence of R1 is independently selected from halogen, cyano, C1-8alkyl, C1-8alkoxy, haloC1-8alkyl and C3-6cycloalkyl;
each occurrence of R2 is independently selected from halogen, cyano, C1-8alkyl, C1-8alkoxy, haloC1-8alkyl, C3-6cycloalkyl, 5 membered heteroaryl, —C(O)NHR, —NHC(O)R, —S(O)2NHR and —C≡CR;
each occurrence of R is independently selected from C1-8alkyl, C3-12cycloalkyl, and C6-14aryl;
‘m’ is an integer ranging from 0 to 3, both inclusive; and
‘n’ is an integer ranging from 0 to 3, both inclusive;
with the proviso that ‘m’ and ‘n’ are not ‘0’ simultaneously.
The compounds of formula (I) exhibit mPGES-1 enzyme inhibition activity and, therefore, are useful for the treatment of pain and inflammation in a variety of diseases or conditions.
The compound “N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)pivalamide”, herein after designated as “compound of formula (II)” is disclosed as Example 100 in the specification of WO 2013/186692. Also disclosed therein, is the process for preparation of compound of formula (II). The structural representation of compound of formula (II) is

Development of a commercial drug candidate involves many steps, such as development of a cost effective synthetic method which is efficient in large scale manufacturing process. Also, in formulation of drug compositions, it is important for the active pharmaceutical ingredient to be in a form in which it can be conveniently handled and processed. Convenient handling is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of subsequent manufacture of pharmaceutical formulations comprising the active pharmaceutical ingredient. The drug development therefore involves research regarding finding suitable pharmaceutically acceptable salt forms of a drug. It may be also desirable to explore various polymorphs of the active pharmaceutical ingredient, which display better handling properties as well as it may also show improved physicochemical as well as pharmacokinetic and pharmacodynamics properties.